Cells of the brain stem nucleus locus coeruleus (LC) are known to contain norepinephrine and project to several cortical regions. Activation of the pathway from LC to the cerebellar Purkinje cells by electrical stimulation results in inhibition of spontaneous firing, both in rat and mouse. The inhibition is accompanied by membrane hyperpolarization and a unique increase in membrane resistance. The inhibition is blocked by prostaglandins, by several phenothiazines, and by prior destruction of adrenergic nerves with 6-OHDA. The inhibitions are accompanied by an increase in cyclic AMP in Purkinje cells, as detected immunocytochemically. The responses to LC persist in the mutant mouse "weaver", which lacks granule cells and parallel fibers, thus validating a direct monosynaptic action of the LC on Purkinje cells. This study was the first to show selective activation of central norepinephrine containing pathway, and thus provides a model for evaluaton of psychoactive drugs on central monoamine systems.